Ultrashort acting hypnotic barbiturates

ABSTRACT

The subject invention concerns novel compounds that are useful as ultrashort acting hypnotic barbiturates. Specifically exemplified are derivatives of barbituric and thiobarbituric acids. They are rapidly metabolized by blood and tissue enzymes to form polar metabolites with no hypnotic activity and which are rapidly eliminated.

CROSS-REFERENCE TO RELATED APPLICATION

This application is aThis application is a Reissue of U.S. applicationSer. No. 10/763,904, now U.S. Pat. No. 7,041,673, which is acontinuation of application U.S. Ser. No. 10/145,601, filed May 13,2002; now U.S. Pat. No. 6,683,086 which is a continuation of applicationU.S. Ser. No. 09/841,738, filed Apr. 24, 2001, now U.S. Pat. No.6,387,914. This application also claims the benefit of U.S. ProvisionalApplication No. 60/199,144, filed Apr. 24, 2000.

BACKGROUND OF THE INVENTION

The principal use of a sedative-hypnotic drug is to produce drowsinessand to promote sleep. Since sedative-hypnotic drugs usually have thecapacity of producing widespread depression of the CNS, these drugs areemployed for various reasons, including as antiepileptic, musclerelaxants, antianxiety drugs, and even to produce amnesia or generalanesthesia. Throughout the world, more prescriptions are written forsedative-hypnotic-antianxiety drugs than for any other class of drugs.

Barbiturates have enjoyed a long period of extensive use assedative-hypnotic drugs. However, except for a few specialized uses,they have been largely replaced by the somewhat safer benzodiazepines.

The barbiturates reversibly depress the activity of all excitabletissues. Not all tissues are affected at the same dose or concentration.The CNS is the most sensitive to the action of barbiturates. Whenbarbiturates are given in sedative or even hypnotic doses, there is verylittle effect on skeletal, cardiac, or smooth muscle. Even in anestheticconcentrations, peripheral effects are weak and do not createdifficulties if the duration of anesthesia is not prolonged. However, ifdepression is extended, serious deficits in cardiovascular and otherperipheral functions can occur.

Barbituric acid (2,4,6-trioxohexahydropyrimidine) and its analogthiobarbituric acid, lack central depressant activity, but the presenceof alkyl or aryl groups at position-5 confers sedative-hypnotic andsometimes other activities. The general structural formula for thebarbiturates and the structures of some of those available in the UnitedStates are shown in Table 1.

TABLE I NAMES AND STRUCTURES OF SOME BARBITURATES AVAILABLE IN THEUNITED STATES.

barbiturate R_(5a) R_(5b) Amobarbital ethyl isopentyl Aprobarbital allylisopropyl Barbital ethyl ethyl Butabarbital ethyl sec-butyl Butalbitalallyl isobutyl Hexobarbital * methyl 1-cyclohexen-1-yl Mephobarbital *ethyl phenyl Metharbital * ethyl ethyl Methohexital * allyl1-methyl-2-pentynyl Pentobarbital ethyl 1-methylbutyl Phenobarbitalethyl phenyl Secobarbital allyl 1-methylbutyl Talbutal allyl sec-butylThiarnylal ** allyl 1-methylbutyl Thiopental ** ethyl 1-methylbutyl * R₃= H, except in hexobarbital, mephobarbital, metharbital, andmethohexital, where it is replaced by CH₃. ** O, except in thiamylal andthiopental, where it is replaced by S.

The carbonyl group at position-2 has acidic properties because of itsposition between the two amido nitrogens, resulting in lactam-lactimtautomerization. The lactim (“enol”) form is favored in alkalinesolutions, resulting in water-soluble salts. The lactam (“keto”) formdoes not dissolve readily in water, although it is quite soluble innon-polar solvents. Compounds in which the oxygen at C-2 is replaced bysulfur are called thiobarbiturates, which are more lipid-soluble thanthe corresponding barbiturates.

In general, structural changes that increase lipid solubility decreaseduration of action, decrease latency to onset of activity, acceleratemetabolic degradation, and often increase hypnotic potency. Introductionof polar groups such as ether, keto, hydroxyl, amino, or carboxyl groupsinto the alkyl side-chains decreases lipid-solubility and abolisheshypnotic activity. Methylation of the N-1 atom increaseslipid-solubility and shortens the duration of action.

Convulsant seizures occurs in various chronic central nervous system(CNS) disorders, particularly epilepsies. These seizures are generallycorrelated with abnormal and excessive EEG (electroencephalogram)discharges. A variety of drugs have been used for treatment of theseseizures. Many of the older drugs are structurally related tophenobarbital, for example, the hydantoins, the deoxybarbiturates, theoxazolidinediones and the succinimides. More recently developedanticonvulsant compounds include the benzodiazepines, iminostilbenes,and valproic acid (Porter R. J., Meldrum, B. S. [1992] “Antiepilepticdrugs” Basic & Clinical Pharmacology, Katzung B. G., Ed., Appleton &Lange, Norwalk, Conn., 5^(th) Edition, pp. 331-349). Additionalcompounds, containing various types of chemical structures and havingvarious pharmacological mechanisms of action are being developed becauseof their anticonvulsant activities (Trevor, A. J., Way, W. L. [1992]“Sedative-hypnotics” Basic & Clinical Pharmacology, Katzung, B. G., Ed.,Appleton & Lange, Norwalk, Conn., 5^(th) Edition, pp. 306-319).

The anticonvulsant drugs currently available in the United States haveseveral shortcomings as therapeutic agents. About one of every threepatients does not obtain significant relief from seizures and a numberof side-effects accompany the therapeutic effects obtained.

The intravenous route of administration is usually reserved for themanagement of convulsive emergencies and for general anesthesia.Barbiturates are bound to plasma albumin to various extends. Lipidsolubility is the primary determinant of binding. They also partitioninto fat in proportion to their lipid solubility. Highly lipid-solublebarbiturates such as thiopental, methohexital, thiamylal, thiohexital,and hexobarbital, undergo a rapid, flow-limited uptake into the mostvascular areas of the brain. Maximal uptake occurs within 30 secondsafter administration. There is then a redistribution into lessvascularized areas of the brain and into other tissues. For such drugsthere is no correlation between duration of action and eliminationhalf-life. The highly vascular kidneys, liver, and heart equilibratealmost as fast as does the brain, so that maximum tissue concentrationoccurs within 1 minute after injection. The less lipid-solublebarbiturates equilibrate much more slowly because their uptake islimited by membrane permeability and not by blood flow. Cerebral uptakeis slower and as long as 20 minutes may be required for sleep to occurafter intravenous administration of barbital or phenobarbital. Atsteady-state, highest concentrations are achieved in fat which then actsas a slow-release reservoir of drug.

All barbiturates are filtered by the renal glomerulus in proportion totheir free concentration in the blood. Barbiturates with a highlipid/water partition coefficient not only are highly protein bound andtherefore are poorly filtered, but also are readily reabsorbed from thelumen of the tubule. The burden of elimination is thus put on thedrug-metabolizing systems. When renal excretion is impaired,barbiturates that depend upon the kidney for elimination may causesevere CNS and cardiovascular depression. Small amounts of barbituratesare also secreted in milk. Metabolism occurs only in the liver foroxybarbiturates and to a small extent in the kidney forthiobarbiturates. The metabolism processes are oxidative in nature,leading to metabolites that are more polar and therefore more rapidlyeliminated. The exception is the oxidative N-demethylation that leads toan active metabolite. The oxidative metabolism occurs mainly at carbon-5where oxidation of radicals form alcohols, ketones, phenols, orcarboxylic acids which may appear in the urine as such or as glucuronicacid conjugates. This process generally terminates biological activity.

Drug toxicity is an important consideration in the treatment of humansand animals. Toxic side effects resulting from the administration ofdrugs include a variety of conditions which range from low grade feverto death. Drug therapy is justified only when the benefits of thetreatment protocol outweigh the potential risks associated with thetreatment. The factors balanced by the practitioner include thequalitative and quantitative impact of the drug to be used as well asthe resulting outcome if the drug is not provided to the individual.Other factors considered include the physical condition of the patient,the disease stage and its history of progression, and any known adverseeffects associated with a drug.

Drug elimination is typically the result of metabolic activity upon thedrug and the subsequent excretion of the drug from the body. Metabolicactivity can take place within the vascular supply and/or withincellular compartments or organs. The liver is a principal site of drugmetabolism. The metabolic process can be categorized into synthetic andnonsynthetic reactions. In nonsynthetic reactions, the drug ischemically altered by oxidation, reduction, hydrolysis, or anycombination of the aforementioned processes. These processes arecollectively referred to as Phase I reactions.

In Phase II reactions, also known as synthetic reactions orconjugations, the parent drug, or intermediate metabolites thereof, arecombined with endogenous substrates to yield an addition or conjugationproduct. Metabolites formed in synthetic reactions are, typically, morepolar and biologically inactive. As a result, these metabolites are moreeasily excreted via the kidneys (in urine) or the liver (in bile).Synthetic reactions include glucuronidation, amino acid conjugation,acetylation, sulfoconjugation, and methylation.

Absorption and redistribution are critical determinants of the time ofonset and duration of anesthetic and hypnotic effects of ultrashort- andshort-acting barbiturates. But it is the elimination rate thatdetermines the time course of residual effects and accumulation of thedrug during repetitive uses. Of all barbiturates currently used in theUnited States for hypnosis, only hexobarbital has a half-life ofelimination that is sufficiently short (2.7-7 hours) for virtuallycomplete elimination to occur within 24 hours. All other barbiturateswill accumulate during repetitive administrations unless appropriateadjustments to dosage are made. Persistence of the drug in plasmafurthermore favors the development of tolerance and abuse.

There is a need in the art for ultrashort acting hypnotic barbituates.

BRIEF SUMMARY OF THE INVENTION

The subject invention provides novel hypnotic barbiturates.Advantageously, the subject invention provides compounds which arereadily metabolized by the physiological metabolic drug detoxificationsystems. Specifically, in a preferred embodiment, the therapeuticcompounds of the subject invention contain a moiety, such as an estergroup, which does not detract from the ability of these compounds toprovide a therapeutic benefit, but which makes these compounds moresusceptible to degradation by hydrolases, particularly serum and/orcytosolic esterases. Because these barbiturates are readily metabolizedthey are both highly effective and short acting. Their metabolism rateis not limited by renal filtration or hepatic uptake, but iscontrollable, predictable, and very rapid.

Degradation of the compounds of the subject invention by enzymes such ashydrolases (esterases, peptidases, lipases, glycosidases, phosphatases,etc.) is particularly advantageous for drug metabolism because theseenzymes are ubiquitously distributed and their activity is not dependenton age, gender, or disease state to the same extent as oxidative hepaticdrug metabolism.

In a preferred embodiment, the major metabolite of the compounds of thesubject invention is a polar, water soluble carboxylate salt which isbiologically inactive and rapidly cleared by the kidneys. Because thesubject compounds are degraded by ubiquitous hydrolases, such asesterases, the compounds are ultra-short-acting hypnotic barbiturateswith rapid clearance from the body, and little, if any, of theafter-effects usually seen with presently available barbiturates. Theironset of activity is governed by their lipid solubility, as in currentlyused barbiturates. In addition, because the active drug does not persistin the plasma, the development of tolerance and abuse is less likely tohappen.

The subject invention further provides methods of treatment comprisingthe administration of the compounds of the subject invention toindividuals in need of treatment with hypnotic barbiturates.

The subject invention further provides compositions and methods usefulto treat convulsions.

In a further embodiment, the subject invention pertains to the breakdownproducts which are formed when the therapeutic compounds of the subjectinvention are acted upon by hydrolases. The major metabolites of thecompounds of the subject invention are polar, water soluble carboxylatesalts. These metabolites are biologically inactive and rapidly clearedby the kidneys. These breakdown products can be used as described hereinto monitor the clearance of the therapeutic compounds from a patient.

In yet a further embodiment, the subject invention provides methods forsynthesizing the therapeutic compounds of the subject invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 describes the first series of compounds where R is an alkyl or anaryl residue containing 1 to about 14 carbon atoms, either linear orbranched.

FIG. 2 describes the other series of compounds where R is an alkyl or anaryl residue containing 1 to about 14 carbon atoms, either linear orbranched.

FIG. 3 depicts the synthesis of the series of compounds shown in FIG. 1.

FIG. 4 depicts the synthesis of the series of compounds shown in FIG. 2.

FIG. 5 shows the synthesis of certain thiobarbiturates of the subjectinvention.

FIG. 6 shows the synthesis of additional compounds of the subjectinvention.

FIG. 7 shows the synthesis of a substituted thiourea.

DETAILED DISCLOSURE

In one embodiment, the subject invention provides new and advantageoushypnotic barbiturates. Advantageously, the therapeutic compounds of thesubject invention are stable in storage but have a shorter half-life inthe physiological environment than other barbiturates; therefore, thecompounds of the subject invention can be used with a lower incidence ofside effects and toxicity.

A further aspect of the subject invention is the provision of compoundsand compositions useful as anticonvulsants. Compounds of Formula Iand/or Formula II (shown below) can be used for this purpose.

Specifically exemplified herein are compounds having the generalchemical structure shown in Table 1, with the exception that a moietysusceptible to degradation by hydrolases is introduced.

In one embodiment, as illustrated by Formula I, the moiety is introducedat the C5 position:

where R₁ hydrogen or (saturated or unsaturated, branched or unbranched)C₁₋₁₄ alkyl or a (substituted or unsubstituted) aryl group. Non-limitingexamples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, ter-butyl, pentyl, isopentyl, neopentyl, cyclohexyl, benzyl,toluyl, menthyl, nor-bornyl, bornyl, and adamantanemethyl. R₂ and R₃are, independently, hydrogen or (saturated or unsaturated, branched orunbranched) C₁₋₄ alkyl. R₄ is hydrogen or (saturated or unsaturated,branched or unbranched) C₁₋₁₄ alkyl or a (substituted or unsubstituted)aryl group. R₆ and R₇ are, independently, hydrogen or (saturated orunsaturated, branched or unbranched) C₁₋₁₄ alkyl. X₁, X₂, and X₃ are,independently, oxygen, nitrogen, or sulfur. Preferably, X₃ is oxygen orsulfur. Finally, n is an integer of from 0 and 5, preferably from 0 and3, and more preferably 0 or 1.

In another embodiment, one example of which is illustrated by FormulaII, the moiety is introduced on one of the nitrogen atoms:

where R₁ is hydrogen or (saturated or unsaturated, branched orunbranched) C₁₋₁₄ alkyl or a (substituted or unsubstituted) aryl group.Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, ter-butyl pentyl, isopentyl, neopentyl, cyclohexyl,benzyl, toluyl, menthyl, nor-bornyl, bornyl, and adamantanemethyl. R₂and R₃ are, independently, hydrogen or (saturated or unsaturated,branched or unbranched) C₁₋₄ alkyl. R₆ is hydrogen or (saturated orunsaturated, branched or unbranched) C₁₋₁₄ alkyl. Alternatively, aswould be appreciated by one skilled in the art having the benefit of theinstant disclosure, the substituent shown in Formula II could be on theother nitrogen with R₆ then being on the nitrogen which is shown inFormula II as being substituted. R₄ and R₅ are, independently, hydrogenor (saturated or unsaturated, branched or unbranched) C₁₋₁₄ alkyl or a(substituted or unsubstituted) aryl group. Examples include ethyl,allyl, phenyl, 1-methylbutyl, sec-butyl, isobutyl, 2-cyclopentenyl,1-cyclohexen-1-yl, 1-methyl- 2-pentynyl, isopentyl, neopentyl,cyclohexyl, benzyl, toluyl, menthyl, nor-bornyl, bornyl, oradamantanemethyl. X₁, X₂, and X₃ are, independently, oxygen, nitrogen,or sulfur. Preferably, X₃ is oxygen or sulfur. Finally, n is an integerof from 0 and 5, preferably from 0 to 3, and most preferably 0 or 1.

As would be appreciated by one skilled in the art, the alkyl and/or arylgroups on the compounds of the subject invention could be substitutedwith a variety of different moieties, so long as the substitutions donot detract from the desired biological activity of the compounds. Thus,the alkyl and aryl groups may be substituted with, for example, C₁₋₁₀alkyl, substituted alkyl groups, substituted or unsubstituted carboxylicacids, substituted or unsubstituted carboxylic esters, halogen,carboxyl, hydroxyl, phosphate, phosphonate, aryl, CN, OH, COOH, NO₂,NH₂, SO₂₋₄, C₁₋₂₀ heteroalkyl, C₂₋₂₀ alkenyl, alkynyl, alkynyl-aryl,alkynyl-heteroaryl, aryl, C₁₋₂₀ alkyl-aryl, C₂₋₂₀ alkenyl-aryl,heteroaryl, C₁₋₂₀ alkyl-heteroaryl, C₂₋₂₀ alkenyl-heteroaryl,cycloalkyl, heterocycloalkyl, C₁₋₂₀ alkyl-heterocycloalkyl, and C₁₋₂₀alkyl-cycloalkyl, any of which may be, optionally, substituted with amoiety selected from the group consisting of C₁₋₆ alkyl, halogen, OH,NH₂, CN, NO₂, COOH, or SO₂₋₄

Compounds of Formula I are particularly preferred for anticonvulsantactivity while compounds of Formula III are particularly preferred forsedative-hypnotic applications.

Advantageously, the presence of a hydrolyzable group in the moleculemakes these compounds biodegradable by, for example, blood and tissueesterases, yielding a carboxylic acid metabolite that is water solubleat physiological pH and therefore rapidly eliminated by renalfiltration. This, in turn, alleviates the after-effects usually observedin patients receiving hypnotic barbiturates. Accordingly, in a specificembodiment, the subject invention provides esterified hypnoticbarbiturates and compositions of these esterified compounds.

FIG. 1 shows a first series of compounds of Formula I of the subjectinvention where R₁ is an alkyl or an aryl residue containing 1 to about14 carbon atoms, either linear or branched. In this series R₆ is ahydrogen, a methyl or an ethyl group. R₄ is alkyl or aryl having between1 and about 14 carbon atoms. X₃ is oxygen or sulfur. Finally, n is aninteger of from 0 and 5, preferably from 0 to 3, and most preferably 0or 1.

FIG. 2 shows another series of compounds of the subject invention whereR₁ is an alkyl or an aryl residue containing 1 to about 14 carbon atoms,either linear or branched. In this series, R₄ is ethyl or allyl. R₅ isalkyl or aryl having between 1 and about 14 carbon atoms. X₃ is oxygenor sulfur. Finally, n is an integer from 0 and 5, preferably from 0 and3, and more preferably 0 or 1.

In a specific embodiment, the compounds of this invention arethiobarbiturates, i.e., the 2-position is a thione as shown in FormulaIII (below). In a preferred embodiment, the compounds of the subjectinvention are substituted at one of the nitrogens, such as position-1.Alternatively, as discussed above, the compounds could be substituted atthe C5 position. The substituent contains a group that is readilycleaved by a non-oxidative hydrolytic enzyme. The presence of this groupmakes these compounds biodegradable by blood and tissue enzymes,yielding a metabolite that is water soluble at physiological pH andtherefore rapidly eliminated by renal filtration. This in turnalleviates the after-effects usually observed in patients receivinghypnotic barbiturates.

Thus, in one embodiment, the compounds of the subject invention have thefollowing structure:

Wherein:

R₁ is hydrogen or an alkyl or an aryl group containing 1 to about 14carbon atoms, either linear or branched, substituted or unsubstituted.Preferred examples are compounds where R₁ is phenyl, benzyl, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ter-butyl, pentyl,isopentyl, neopentyl, cyclohexyl, benzyl, toluyl, menthyl, nor-bornyl,bornyl, lauryl, myristyl, or adamantanemethyl.

X₁ and X₂ are, independently, O, S, or N.

R₄ and R₅ are, independently, saturated or unsaturated alkyl or arylhaving between 1 and about 14 carbon atoms. Preferred examples areethyl, allyl, phenyl, benzyl, 1-methylbutyl, sec-butyl, isobutyl,2-cyclopentenyl, 1-cyclohexen-1-yl, 1-methyl-2-pentynyl, isopentyl, andneopentyl.

R₆ is hydrogen or alkyl having between 1 and about 14 carbon atoms.Preferably, R₆ is hydrogen, methyl, or ethyl. Most preferably, R₆ ishydrogen.

Finally, n is an integer of from 0 and 5, preferably from 0 and 3, andmore preferably 0 or 1.

In a preferred embodiment of the subject invention, hypnoticbarbiturates are provided which contain an ester group which is actedupon by esterases thereby breaking down the compound and facilitatingits efficient removal from the treated individual. In a preferredembodiment the therapeutic compounds are metabolized by the Phase I drugdetoxification system.

This invention includes pharmaceutical compositions comprising any ofthe compounds of Formulas I and II (or analogs thereof), alone or incombination with each other or other active compounds, in an amounteffective for providing hypnotic barbiturate effect and/or amelioratingconvulsions or the symptoms of convulsions or in an amount effective forameliorating anxiety or its symptoms. Pharmaceutical compositions ofthis invention include various pharmaceutical dosage forms formulatedfor oral or transdermal administration or administration by injection toa mammal and include among others, tablets, pills, capsules, andinjectable solutions or suspensions. Pharmaceutical compositions of thisinvention contain from about 0.1% to about 99% of one or more compoundsof Formula I or II (or an analog thereof). The pharmaceuticalcompositions preferably include those that contain from about 1% toabout 90% of one or more of the compounds of Formula I or II.

This invention is also directed to methods of providing a hypnoticbarbiturate effect and/or preventing or treating convulant seizures inmammals, by administration to the mammal of an amount of a compound ofFormula I or II (or an analog thereof) effective for preventing orameliorating convulsant seizures or the symptoms of such seizures. Thisinvention is further directed to methods of preventing or treatinganxiety in mammals by administration to the mammal of an amount of acompound of Formula I or II (or an analog thereof) or mixtures thereofeffective for preventing or ameliorating anxiety or the symptoms ofanxiety. Administration can be by any known route including, but notlimited to, injection or oral or transdermal routes.

The anticonvulsant properties can be confirmed by pharmacologic testing,utilizing two standard animal models of epilepsy: the pentylenetetrazole(PTZ)-induced seizure procedure and the maximal electroshock test (MES).General descriptions of such testing can be found in J. F. Reinhard andJ. F. Reinhard, Jr., “Experimental Evaluation of Anticonvulsants” inAnticonvulsants, J. A. Vida, Ed., Academic Press, New York, N.Y., 1977.

In general, compounds may be used in treating epilepsy in mammalsincluding humans. Medical aspects of the treating of epilepsy aredescribed in greater detail by Rail and Schleifer in Goodman andgilman's The Pharmacological Basis of Therapeutics, 8^(th) Ed.; GoodmanGilman, A.; Rail, T. W.; Nies, A. S.; Taylor, P., Eds.; Pergamon Press:New York, 1990; pp. 436-462.

A further aspect of the subject invention pertains to the breakdownproducts which are produced when the therapeutic compounds of thesubject invention are acted upon by hydrolases. The presence of thesebreakdown products in the urine or serum can be used to monitor the rateof clearance of the therapeutic compound from a patient.

The subject invention further provides methods of synthesizing theunique and advantageous therapeutic compounds of the subject invention.Particularly, methods of producing less toxic therapeutic agentscomprising introducing ester groups into therapeutic agents (targetdrugs) are taught. The ester linkage may be introduced into the compoundat a site which is convenient in the manufacturing process for thetarget drug. Additionally, the sensitivity of the ester linkage may bemanipulated by the addition of side groups which hinder or promote thehydrolytic activity of the hydrolases or esterases responsible forcleaving the drug at the ester locus. Methods of adding such sidegroups, as well as the side groups themselves, are well known to theskilled artisan and can be readily carried out utilizing the guidanceprovided herein.

The compounds of this invention have therapeutic properties similar tothose of the unmodified parent compounds. Accordingly, dosage rates androutes of administration of the disclosed compounds are similar to thosealready used in the art and known to the skilled artisan (see, forexample, Physicians' Desk Reference, 54^(th) Ed., Medical EconomicsCompany, Montvale, N.J., 2000).

The compounds of the subject invention can be formulated according toknown methods for preparing pharmaceutically useful compositions.Formulations are described in detail in a number of sources which arewell known and readily available to those skilled in the art. Forexample, Remington's Pharmaceutical Science by E. W. Martin describesformulations which can be used in connection with the subject invention.In general, the compositions of the subject invention are formulatedsuch that an effective amount of the bioactive compound(s) is combinedwith a suitable carrier in order to facilitate effective administrationof the composition.

In accordance with the subject invention, pharmaceutical compositionsare provided which comprise, as an active ingredient, an effectiveamount of one or more of the compounds and one or more non-toxic,pharmaceutically acceptable carriers or diluents. Examples of suchcarriers for use in the invention include ethanol, dimethyl sulfoxide,glycerol, silica, alumina, starch, and equivalent carriers and diluents.

Further, acceptable carriers can be either solid or liquid. Solid formpreparations include powders, tablets, pills, capsules, cachets,suppositories and dispersible granules. A solid carrier can be one ormore substances which may act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents or encapsulating materials.

The disclosed pharmaceutical compositions may be subdivided into unitdoses containing appropriate quantities of the active component. Theunit dosage form can be a packaged preparation, such as packetedtablets, capsules, and powders in paper or plastic containers or invials or ampoules. Also, the unit dosage can be a liquid basedpreparation or formulated to be incorporated into solid food products,chewing gum, or lozenge.

The term “individual(s)” is defined as a single mammal to which isadministered a compound of the present invention. The mammal may be, forexample a mouse, rat, pig, horse, rabbit, goat, pig, cow, cat, dog, orhuman. In a preferred embodiment, the individual is a human.

Modifications of the compounds disclosed herein can readily be made bythose skilled in the art. Thus, analogs, derivatives, and salts of theexemplified compounds are within the scope of the subject invention.With a knowledge of the compounds of the subject invention, and theirstructures, skilled chemists can use known procedures to synthesizethese compounds from available substrates.

As used in this application, the term “analogs” refers to compoundswhich are substantially the same as another compound but which may havebeen modified by, for example, adding additional side groups. The term“analogs” as used in this application also may refer to compounds whichare substantially the same as another compound but which have atomic ormolecular substitutions at certain locations in the compound.

Analogs of the exemplified compounds can be readily prepared usingcommonly known, standard reactions. These standard reactions include,but are not limited to, hydrogenation, methylation, acetylation, andacidification reactions. For example, new salts within the scope of theinvention can be made by adding mineral acids, e.g., HCl, H₂SO₄, etc.,or strong organic acids, e.g., formic, oxalic, etc., in appropriateamounts to form the acid addition salt of the parent compound or itsderivative. Also, synthesis type reactions may be used pursuant to knownprocedures to add or modify various groups in the exemplified compoundsto produce other compounds within the scope of the invention.

The synthesis of certain compounds of the subject invention is describedin FIGS. 3 and 4. The synthesis of series 1 (FIG. 1) is described inFIG. 3, where a substituted diethyl malonate compound is deprotonated bysodium ethoxide in ethanol and reacted with an ester of chloroaceticacid in order to give the intermediate II. This intermediate is in turncondensed with an N-substituted urea or thiourea in ethanol/sodiumethoxide in order to yield the desired product III. Synthesis of series2 (FIG. 2) is described in FIG. 4. In this series, an alkyliso(thio)cyanatoacetate or an alkyl iso(thio) cyanate is reacted withammonia in order to form the corresponding urea (thiourea) IV or V,respectively. These in turn are reacted with a disubstituted diethylmalonate in order to yield the desired compounds.

The synthesis of certain thiobarbituates of the subject invention isdescribed in FIG. 5, where a 2,2-disubstituted malonyl chloride reactswith a N-substituted or a N,N-disubstituted thiourea to give thecompounds of this invention. Alternatively, as shown in FIG. 6, a2,2-disubstituted malonic acid reacts with the substituted thiourea inthe presence of phosphorus oxychloride to give compounds of thisinvention. In a closely related synthetic method, acetic anhydride canbe substituted for phosphorus oxychloride, thus giving again the desiredthiobarbiturate product.

The synthesis of a substituted thiourea is described in FIG. 7, where aγ-aminoacid ester reacts with thiophosgene in the presence of a basesuch as triethylamine in methylene chloride, or such as sodiumbicarbonate in a methylene chloride/water biphasic system to give aisothiocyanatoalkylcarboxylate ester. The aqueous phase can also beomitted, and the reaction can take place in a suspension of calciumcarbonate in methylene chloride. In a typical procedure, 2 equivalentsof thiophosgene in toluene or dichloromethane is added to an iced-cooledsolution of the aminoacid in methylene chloride containing calciumcarbonate as a solid. The reaction is usually complete after 10 to 30minutes of rapid stirring.

The synthesis of the 2,2-disubstituted malonyl chloride compounds usedaccording to the subject invention can be done according to well knownprocedures. Typically, diethyl malonate is alkylated at the 2-positionusing 1 equivalent of sodium ethoxide as a base and 1 equivalent of analkyl halide in ethanol. The resulting monoalkylated product can then bealkylated again using another equivalent of sodium ethoxide and anotherequivalent of an alkyl halide in ethanol. The resulting2,2-disubstituted diethyl malonate is then hydrolyzed to the diacidusing 2 equivalents of lithium hydroxide in ethanol/water. The productis isolated as a dicarboxylic acid upon acidification with dilute HCl orwith citric acid. This diacid in turn is reacted with phosphoruspentachloride to give the 2,2-disubstituted malonyl chloride used in thesynthesis of the thiobarbiturates.

Materials and Methods

Reagents were bought from Aldrich Chemical Company (Milwaukee, Wis.)unless stated otherwise. Diethyl Δ²-cyclopentylmalonate was preparedaccording to the procedure described in Organic Syntheses IV:291.

Following are examples which illustrate procedures for practicing theinvention. These examples should not be construed as limiting. Allpercentages are by weight and all solvent mixtures proportions are byvolume unless otherwise noted.

EXAMPLE 1 Esters of Chloroacetic Acid

Adamantanemethyl chloroacetate 1 neopentyl chloroacetate 2, isobutylchloroacetate 3, and cyclohexyl chloroacetate 4 were prepared asfollows: To a solution of chloroacetyl chloride (10 mmoles) in drymethylene chloride was added an equimolar amount of eitheradamantanemethanol, neopentanol, isobutanol, or cyclohexanol. After 2hours at room temperature the solvent was removed and the product wasdistilled under reduced pressure to give a colorless liquid.

EXAMPLE 2 Esters of Diethyl Phenylmalonylacetic Acid

Adamantanemethyl, neopentyl, isobutyl, and cyclohexyl esters 5,6,7, and8, respectively were prepared as follows: To 0.1 mole of sodium ethoxidein absolute ethanol (200 ml) was added 0.1 moles of diethylphenylmalonic acid followed by 0.1 mole of the appropriate ester ofchloroacetic acid described above. After refluxing for 4 hours, themixture was filtered and the solvent was evaporated. The product wasrecrystallized from hot ethanol.

EXAMPLE 3 Esters of Diethyl Δ²-cyclopentylmalonylacetic Acid

Adamantanemethyl, neopentyl, isobutyl, and cyclohexyl esters 9,10,11,and 12, respectively were prepared as follows: To 0.1 mole of sodiumethoxide in absolute ethanol (200 ml) was added 0.1 moles of diethylΔ²-cyclopentylmalonic acid followed by 0.1 mole of the appropriate esterof chloroacetic acid described above. After refluxing for 4 hours, themixture was filtered and the solvent was evaporated. The product wasrecrystallized from hot ethanol.

EXAMPLE 4 3-methyl-4,6-dioxo-5-phenylhexahydropyrimidine-5-acetic Acid,Adamantanemethyl Ester: 13 adamantan- 1 -ylmethyl ( 1 -methyl- 4,6-dioxo- 5 -phenyl- 2 -thioxohexahydropyrimidin- 5 -yl)acetate: 13

To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole ofthe ester 5 followed by 0.1 mole of dry N-methylthiourea in hot absoluteethanol. After refluxing for 8 hours, hot water (500 ml) is added,followed by enough HCl to make the solution acidic. The solution is thenfiltered and cooled in an ice-bath overnight. The white product iscollected by filtration and dried in vacuo.

EXAMPLE 5 3-methyl-4,6-dioxo-5-phenylhexahydropyrimidine-5-acetic Acid,Neopentyl Ester: 14 neopentyl 2-( 1 -methyl- 4,6 -dioxo- 5 -phenyl- 2-thioxohexahydropyrimidin- 5 -yl)acetate: 14

To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole ofthe ester 6 followed by 0.1 mole of dry N-methylthiourea in hot absoluteethanol. After refluxing for 8 hours, hot water (500 ml) is added,followed by enough HCl to make the solution acidic. The solution is thenfiltered and cooled in an ice-bath overnight. The white product iscollected by filtration and dried in vacuo.

EXAMPLE 6 3-methyl-4,6-dioxo-5-phenylhexahydropyrimidine-5-acetic Acid,Isobutyl Ester: 15 isobutyl 2-( 1 -methyl- 4,6 -dioxo- 5 -phenyl- 2-thioxohexahydropyrimidin- 5 -yl)acetate: 15

To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole ofthe ester 7 followed by 0.1 mole of dry N-methylthiourea in hot absoluteethanol. After refluxing for 8 hours, hot water (500 ml) is added,followed by enough HCl to make the solution acidic. The solution is thenfiltered and cooled in an ice-bath overnight. The white product iscollected by filtration and dried in vacuo.

EXAMPLE 7 3-methyl-4,6-dioxo-5 phenylhexahydropyrimidine-5-acetic Acid,Cyclohexyl Ester: 16 cyclohexyl 2-( 1 -methyl- 4,6 -dioxo- 5 -phenyl- 2-thioxohexahydropyrimidin- 5 -yl)acetate: 16

To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole ofthe ester 8 followed by 0.1 mole of dry N-methylthiourea in hot absoluteethanol. After refluxing for 8 hours, hot water (500 ml) is added,followed by enough HCl to make the solution acidic. The solution is thenfiltered and cooled in an ice-bath overnight. The white product iscollected by filtration and dried in vacuo.

EXAMPLE 83-methyl-4,6-dioxo-5-δ²-cyclopentylhexahydropyrimidine-5-acetic AcidAdamantanemethyl Ester: 17 adamantan- 1 -ylmethyl ( 5 -cyclopent- 2 -en-1 -yl- 1 -methyl- 4,6 -dioxo- 2 -thioxohexahydropyrimidin- 5-yl)acetate: 17

To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole ofthe ester 9 followed by 0.1 mole of dry N-methylthiourea in hot absoluteethanol. After refluxing for 8 hours, hot water (500 ml) is added,followed by enough HCl to make the solution acidic. The solution is thenfiltered and cooled in an ice-bath overnight. The white product iscollected by filtration and dried in vacuo.

EXAMPLE 93-methyl-4,6-dioxo-5-δ²-cyclopentylhexahydropyrimidine-5-acetic AcidNeopentyl Ester: 18 neopentyl 2-( 5 -(cyclopent- 2 -enyl)- 1 -methyl-4,6 -dioxo- 2 -thioxohexahydropyrimidin- 5 -yl)acetate: 18

To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole ofthe ester 10 followed by 0.1 mole of dry N-methylthiourea in hotabsolute ethanol. After refluxing for 8 hours, hot water (500 ml) isadded, followed by enough HCl to make the solution acidic. The solutionis then filtered and cooled in an ice-bath overnight. The white productis collected by filtration and dried in vacuo.

EXAMPLE 103-methyl-4,6-dioxo-5-δ²-cyclopentylhexahydropyrimidine-5-acetic AcidIsobutyl Ester: 19 isobutyl 2-( 5 -(cyclopent- 2 -enyl)- 1 -methyl- 4,6-dioxo- 2 -thioxohexahydropyrimidin- 5 -yl)acetate: 19

To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole ofthe ester 11 followed by 0.1 mole of dry N-methylthiourea in hotabsolute ethanol. After refluxing for 8 hours, hot water (500 ml) isadded, followed by enough HCl to make the solution acidic. The solutionis then filtered and cooled in an ice-bath overnight. The white productis collected by filtration and dried in vacuo.

EXAMPLE 113-methyl-4,6-dioxo-5-δ²-cyclopentylhexahydropyrimidine-5-acetic AcidCyclohexyl Ester: 20 cyclohexyl 2-( 5 -(cyclopent- 2 -enyl)- 1 -methyl-4,6 -dioxo- 2 -thioxohexahydropyrimidin- 5 -yl)acetate: 20

To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole ofthe ester 12 followed by 0.1 mole of dry N-methylthiourea in hotabsolute ethanol. After refluxing for 8 hours, hot water (500 ml) isadded, followed by enough HCl to make the solution acidic. The solutionis then filtered and cooled in an ice-bath overnight. The white productis collected by filtration and dried in vacuo.

EXAMPLE 12 Thiourea (N-acetic Acid Ethyl Ester): 21

To 0.1 mole of ethyl isothiocyanatoacetate in ethanol (50 ml) is added50 ml of a 2M ethanolic solution of ammonia. After 2 hours at roomtemperature, the precipitated product is collected by filtration andused in the next step.

EXAMPLE 13 N-ethoxycarbonylthiourea: 2 22

To 0.1 mole of ethoxycarbonyl isothiocyanate in ethanol (50 ml) is added50 ml of a 2M ethanolic solution of ammonia. After 2 hours at roomtemperature, the precipitated product is collected by filtration andused in the next step.

EXAMPLE 144,6-dioxo-5-allyl-5-isopentylhexahydropyrimidine-3-aceticacid, EthylEster: 23 ethyl 2-( 5 -allyl- 5 -isopentyl- 4,6 -dioxo- 2-thioxotetrahydropyrimidin- 1 ( 2H)-yl)acetate: 23

Compound 21 (10 mmoles) is dissolved in ethanol containing 10 mmoles ofsodium ethoxide. To this is added 10 mmoles of diethyl(allylisopentyl)malonate and the mixture is refluxed for 8 hours. Theproduct crystallized upon cooling.

EXAMPLE 153-ethoxycarbonyl-4,6-dioxo-5-allyl-5-isopentylhexahydropyrimidine: 24ethyl 5-allyl- 5 -isopentyl- 4,6 -dioxo- 2 -thioxotetrahydropyrimidine-1 ( 2H)-carboxylate: 24

Compound 22 (10 mmoles) is dissolved in ethanol containing 10 mmoles ofsodium ethoxide. To this is added 10 mmoles of diethyl(allylisopentyl)malonate and the mixture is refluxed for 8 hours. Theproduct crystallized upon cooling.

EXAMPLE 16 Hypnotic Activity in Rats

When compounds 13 to 20, 23, and 24 are administered to ratsintraperitoneally at a dose of 50 mg/kg, they induce sleep within 10minutes after administration. The hypnosis is of short duration (lessthan one hour), consistent with the scope of this invention.

EXAMPLE 17 2-thiohydantoin:

9.89 g of Glycine methyl ester, hydrochloride salt, and 6.9 g ofpotassium thiocyanate are heated at 150° C. in an oil bath withoccasional stirring for 15 minutes or until a brownish melt is obtained.The reaction is cooled down and 100 ml of ethanol is added. Stir at roomtemperature for 4 hours. Filter off the precipitate and wash it withethanol. The filtrate is evaporated and the residue is crystallized fromacetone and methyl ter-butyl ether.

EXAMPLE 18 1-Carboxymethylthiourea:

5.8 g of 2-Thiohydantoin and 15 g of barium hydroxide hydrate arerefluxed in 200 ml of water for 1 hour. The mixture is cooled in an icebath and acidified to pH 2.0 with 10% sulfuric acid. Filter throughcelite. The filtrate is then continuously extracted for 2 days withethyl ether. The extract is evaporated and the residual water is removedby co-distillation with methanol/ethyl acetate. The product is thencrystallized from methanol/ethyl acetate.

EXAMPLE 19 General Method for the Preparation ofIsothiocyanato-γ-alkylcarboxylate Esters

The γ-aminoalkylcarboxylate ester and 1.1 equivalent amount ofthiophosgene are added to a stirring mixture of methylene chloride (100ml) and saturated sodium bicarbonate solution (100 ml). After stirringfor 2 hours, the organic phase is washed with 100 ml water, dried overmagnesium sulfate, and evaporated. The yield of product is nearlyquantitative. The following compounds were prepared from this method:

-   Methyl isothiocyanato-2-acetate (from glycine methyl ester, HCl)-   Ethyl isothiocyanato-2-acetate (from glycine ethyl ester, HCl)-   Neopentyl isothiocyanato-2-acetate from glycine neopentyl ester,    HCl)-   Nor-Bornyl isothiocyanato-2-acetate from glycine Norbornyl ester,    HCl)-   Methyl isothiocyanato-4-butyrate (from 4-aminobutyric acid methyl    ester, HCl)-   Methyl isothiocyanato-2-methyl-2-propionate (from    2-amino-2-methylpropionic acid methyl ester, HCl)-   Benzyl isothiocyanato-2-methyl-2-propionate (from    2-amino-2-methylpropionic acid benzyl ester, HCl)-   Methyl isothiocyanato-2-propionate (from alanine methyl ester, HCl)-   ter-Butyl isothiocyanato-2-propionate from alanine ter-butyl ester,    HCl)-   ter-Butyl isothiocyanato-2-acetate (from glycine ter-butyl ester,    HCl)-   Methyl isothiocyanato-12-laurate (from 12-aminolauric acid methyl    ester, HCl)-   Methyl isothiocyanato-2-myristate (from 14-aminomyristic acid methyl    ester, HCl)-   Isothiocyanato-4-butyric acid amide from 4-aminobutyric acid amide)-   Isothiocyanato-4-butyric acid N,N-dimethylamide (from 4-aminobutyric    acid N,N-dimethylamide)-   Isothiocyanato-4-butyric acid morpholinamide (from 4-aminobutyric    acid morpholinamide)

EXAMPLE 20 General Method for the Preparation of the 1-substitutedThiourea

The isothiocyanatoalkyl carboxylate esters and amides described inexample 3 are dissolved in THF and one equivalent amount of ammonia inmethanol/water is added dropwise at 0° C. The solvent is evaporated andthe residue is purified by flash chromatography through a short plug ofsilica. An example is given for the preparation of1-Carbethoxymethylthiourea, where 2.3 ml of 28-30% Aqueous ammoniasolution in 10 ml of methanol is added dropwise to an ice-cooledsolution of 5 g ethyl isothiocyanato-2-acetate in 50 ml of THF. Themixture is stirred at room temperature for another 2 hours and isevaporated. The residual water is removed by co-distillation with ethylacetate and is filtered through a short plug of silica, eluting withmethanol/methylene chloride 03:97. The product (4.83 g) is an orangesolid.

EXAMPLE 21 General Method for the Preparation of1-substituted-thiobarbiturates

Equivalent amounts of 2,2-disubstituted malonyl chloride and1-substituted thiourea are mixed and stirred at 80° C. overnight. Themixture is then diluted with water and extracted with an organicsolvent. The crude product is either distilled or is precipitated byacidification of its sodium salt. The following are examples ofcompounds made after this procedure:

1-Carbethoxymethyl-5,5-diethylthiobarbituric acid: 39 g ofDiethylmalonyl chloride is mixed with 64 g of 2-thiohydantoic acid ethylester. Heat at 80° C. for 18 hours. Cool down to room temperature andthen dilute with 200 ml of water. Extract with dichloromethane and thenevaporate the solvent. The oily residue is dissolved in 1N NaOH and isthen precipitated out by slow addition of 1N HCl. The product ispurified by solubilizing again in 1N NaOH and then precipitating it with1N HCl.1-carbethoxymethyl-5-ethyl-5-isoamylthiobarbituric acid: 35 g of2-Ethyl-2-isoamylmalonyl chloride, prepared from2-ethyl-2-isoamylmalonic acid (52 g) and phosphorus pentachloride (148g), and thiohydantoic acid ethyl ester are mixed and heated at 80° C.for 18 hours. Cool to room temperature and then pour into 200 ml of coldwater. Extract with dichloromethane. Evaporate the solvent and thendistill the oily residue at 1 mm Hg.1-Carbethoxymethyl-5,5-dibutylthiobarbituric acid: 44 g ofDibutylmalonyl chloride is mixed with 64 g of 2-thiohydantoic acid ethylester and is stirred at 80 C. for 18 hours. Cool down to roomtemperature and then dilute with 200 ml of water. Extract withdichloromethane and then evaporate the solvent. The oily residue isdissolved in 1N NaOH and is then precipitated out by slow addition of 1NHCl. The product is purified by solubilizing again in 1N NaOH and thenprecipitating it with 1N HCl. The following compounds were also madeafter the same procedure:

-   1-carbomethoxytridecyl-5-ethyl-5-(2-pentyl)thiobarbituric acid-   1-carbomethoxyundecyl-5-ethyl-5-(2-pentyl)thiobarbituric acid-   1-carbo(neopentyloxy)methyl-5,5-dibutylthiobarbituric acid-   1-carbo(norbornyloxy)methyl-5-ethyl-5-isoamylthiobarbituric acid-   1-(4-butyric acid morpholinamide)-5,5-dipropylthiobarbituric acid-   1-(4-butyric acid amide)-5,5-dipropylthiobarbituric acid-   1-(4-butyric acid N,N-dimethylamide)-5,5-dipropylthiobarbituric acid-   1-(2-propionic acid ter-butyl    ester)-5-ethyl-5-cyclopentylthiobarbituric acid-   1-(2-methyl-2-propionic acid benzyl    ester)-5,5-dipropylthiobarbituric acid-   1-carbomethoxy-5,5-dibutylthiobarbituric acid-   1-carbomethoxy-5,5-dipropylthiobarbituric acid-   1-carbomethoxy-5,5-diethylthiobarbituric acid-   1-carbomethoxy-5-allyl-5-(2-pentyl)thiobarbituric acid-   1-carbomethoxy-5-ethyl-5-(2-pentyl)thiobarbituric acid

EXAMPLE 22 Preparation of Salts

The thiobarbiturate is dissolved in an equivalent amount of 0.8Nethanolic sodium hydroxide solution. Most of the solvent is thenevaporated and the salt is precipitated with hexane. Filter and washwith more hexane. Dry in vacuo.

It should be understood that the examples, reaction schemes, andembodiments described herein are for illustrative purposes only and thatvarious modifications or changes in light thereof will be suggested topersons skilled in the art and are to be included within the spirit andpurview of this application and the scope of the appended claims.

1. A compound selected from the group consisting of:3-methyl-4,6-dioxo-5-phenylhexahydropyrimidine-5-acetic Acid,Adamantanemethyl Esteradamantan- 1 -ylmethyl( 1 -methyl- 4,6 -dioxo- 5-phenyl- 2 -thioxohexahydropyrimidin- 5 -yl)acetate

3-methyl-4,6-dioxo-5-phenylhexahydropyrimidine-5-acetic Acid, CyclohexylEstercyclohexyl 2-( 1 -methyl- 4,6 -dioxo- 5 -phenyl- 2-thioxohexahydropyrimidin- 5 -yl)acetate

3-methyl-4,6-dioxo-5-δ²-cyclopentylhexahydropyrimidine-5-acetic AcidAdamantanemethyl Esteradamantan- 1 -ylmethyl( 5 -cyclopent- 2 -en- 1-yl- 1 -methyl- 4,6 -dioxo- 2 -thioxohexahydropyrimidin- 5 -yl)acetate

3-methyl-4,6-dioxo-5-δ²-cyclopentylhexahydropyrimidine-5-acetic AcidCyclohexyl Estercyclohexyl 2-( 5 -(cyclopent- 2 -enyl)- 1 -methyl- 4,6-dioxo- 2 -thioxohexahydropyrimidin- 5 -yl)acetate

and pharmaceutically acceptable salts thereof.
 2. A compound selectedfrom the group consisting of:3-methyl-4,6-dioxo-5-phenylhexahydropyrimidine-5-acetic Acid, NeopentylEsterneopentyl 2-( 1 -methyl- 4,6 -dioxo- 5 -phenyl- 2-thioxohexahydropyrimidin- 5 -yl)acetate

3-methyl-4,6-dioxo-5-phenylhexahydropyrimidine-5-acetic Acid IsobutylEsterisobutyl 2-( 1 -methyl- 4,6 -dioxo- 5 -phenyl- 2-thioxohexahydropyrimidin- 5 -yl)acetate

3-methyl-4,6-dioxo-5-δ²-cyclopentylhexahydropyrimidine-5-acetic AcidNeopentyl Esterneopentyl 2-( 5 -(cyclopent- 2 -enyl)- 1 -methyl- 4,6-dioxo- 2 -thioxohexahydropyrimidin- 5 -yl)acetate

3-methyl-4,6-dioxo-5-δ²-cyclopentylhexahydropyrimidine-5-acetic AcidIsobutyl Esterisobutyl 2-( 5 -(cyclopent- 2 -enyl)- 1 -methyl- 4,6-dioxo- 2 -thioxohexahydropyrimidin- 5 -yl)acetate

and pharmaceutically acceptable salts thereof.
 3. A compound selectedfrom the group consisting of:4,6-dioxo-5-allyl-5-isopentylhexahydropyrimidine-3-aceticacid, EthylEsterethyl 2-( 5 -allyl- 5 -isopentyl- 4,6 -dioxo- 2-thioxotetrahydropyrimidin- 1 ( 2H)-yl)acetate

3-ethoxycarbonyl-4,6-dioxo-5-allyl-5-isopentylhexahydropyrimidineethyl5-allyl- 5 -isopentyl- 4,6 -dioxo- 2 -thioxotetrahydropyrimidine- 1 (2H)-carboxylate

and pharmaceutically acceptable salts thereof.
 4. A compositioncomprising the compound according to claim 1 and a pharmaceuticallyacceptable carrier or diluent.
 5. A composition comprising the compoundaccording to claim 2 and a pharmaceutically acceptable carrier ordiluent.
 6. A composition comprising the compound according to claim 3and a pharmaceutically acceptable carrier or diluent.